Prostate cancer is the second leading cause of cancer death in men in the United States. Prostate specific antigen (PSA) is a tumor marker that has been used in every aspect of the disease, including screening, treatment planning and surveillance. However, PSA is fraught with many uncertainties and is under constant interrogation. Therefore, there is a critical need for the development of an alternative tumor marker. Recently, the presence of the TMPRSS2:ERG fusion gene has been demonstrated in approximately half of all prostate cancers. This recurrent genomic rearrangement is very likely associated with prostate cancer development. We have established a microarray-based assay that can screen a broad range of fusion variants. We hypothesize that TMPRSS2:ERG can be used as a biomarker and that identification of the specific fusion junction can be used for designing quantitative PCR assays to assess "tumor load" in the urine and blood. This biomarker is an excellent alternative to PSA, as these fusion genes are truly cancer specific and appear to be associated with the pathogenesis of prostate cancer. Furthermore, we will also study the transformation activity of the fusion variants to better understand their role in prostate cancer development. Our specific aims are (1) Determine TMPRSS2:ERG fusion variants in primary prostate tumor and corresponding urine;(2) Correlate the presence/absence of specific TMPRSS2:ERG fusion variants in primary tumor and urine with clinical outcome;(3) Characterize the transformation activities of various TMPRSS2:ERG protein products. A true cancer-specific biomarker that mirrors "tumor load" (an analog to "viral load" for managing HIV patients) will be very useful for assessing aggressiveness of disease and response to therapy. The success of this proposal will significantly improve decision making for patients with prostate cancer. PUBLIC HEALTH RELEVANCE: There is a critical need for the development of an alternative tumor marker for prostate cancer, the second leading cause of cancer death in men in the United States. The currently used biomarker, prostate specific antigen (PSA), is fraught with many uncertainties and is under constant interrogation, leading us to establish a sensitive assay on a true prostate cancer-specific fusion gene for clinical application. The success of this proposal will significantly improve decision making for patients with prostate cancer.